State of the art for radiotherapy of SCCHN

Less side effects Cured More organ & function preservation Head & neck cancer = 42 000 new cases / year in Europe Not cured Local failure Distant failure More effective systemic treatment

Advances in radiotherapy for HNC 1) Lessons from randomized trials 2) IMRT : beyond parotid sparing? 3) New approaches?

The more intense RT-CT, the better? Phase 3 randomised GORTEC 99-02 trial Randomized trials EBM level 1 MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Other randomized trials

Lessons from randomized trials : 70 Gy / 7 weeks alone = Perhaps the worst we can do! Adaptive RT RT-CT + X%? Altered fractionation Induction CT Cetuximab + RT + 13% + 10% + X%? + 10%

Lessons from randomized trial (II) Level of Evidence (EBM-1) Altered Fractionation Chemo-RT Hypoxia targeting Other EGFr targeting Cetuximab Induction Chemo IMRT Use in routine practice

Concomitant chemo-rt More efficient on tumor control / survival But also more side effects ++! = is considered in Europe as a standard of care

MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Risk of recurrence (%) 100 80 60 40 20 Why CT-RT is a standard treatment? Chemotherapy Control Local failure 63.2 % 49.7 % Distant failure 18.9 % 16 % RT Concominant RT + 5FU-platin 0 0 1 2 3 4 5 6 7 8 Time from randomisation (Years) Pignon et al Radiother Oncol 2009

Which type of concomitant CT-RT? Which drugs? Increasing / decreasing the dose intensity?

MACH-NC Meta-Analysis of Chemotherapy in Head & Neck Cancer Type of hemotherapy Survival by type of concomitant CT No. Deaths / No. Entered LRT+CT LRT O-E Variance Hazard Ratio HR [95% CI] p of interaction (a) Poly chemotherapy 5-FU and Platin 602 / 940 695 / 931-92.2 317.6 0.75 [0.67;0.84] p = 0.41 5-FU or Platin 495 / 743 543 / 795-45.8 250.0 0.83 [0.74;0.94] Neither 5-FU nor Platin 62 / 115 85 / 129-11.1 35.0 0.73 [0.52;1.01] Subtotal (a) 1159 / 1798 1323 / 1855-149.0 602.6 0.78 [0.72;0.85] (b) Mono chemotherapy Mono cisplatin 703 / 1151 739 / 1059-102.6 341.8 Mono Other 1309 / 1875 1327 / 1877-74.8 643.3 Subtotal (b) 2012 / 3026 2066 / 2936-177.4 985.1 0.74 [0.67;0.82] 0.89 [0.82;0.96] 0.84 [0.78;0.89] p = 0.006 Total (a b) 3171 / 4824 3389 / 4791-326.4 1587.7 0.81 [0.78;0.86] Test for heterogeneity: 2 1 = 1.69 p = 0.19 0.5 1.0 2.0 LRT+CT better LRT better

Which type of concomitant CT-RT? (I) Which drugs? Decreasing the dose intensity of Chemo?

A randomized trial (USA, 1987) included in the MACH-NC database Concomitant 20 mg / m2 / week : no benefit 1.0 OS ; p=0.81 Probability of survival 0.8 0.6 0.4 0.2 Cisplatin 20mg/m 2 qw + RT (n=149) RT alone (n=159) 0.0 0 2 4 6 8 10 12 14 Time (years)

Gortec 99-02 trial, 2 versus 3 cycles (257 patients who received at least 68 Gy) 1.00 0.90 2 chemo cycles 1.00 0.90 2 chemo cycles 3 chemo cycles 0.80 3 chemo cycles 0.80 At risk 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 3 cycles 2 cycles 0 1 2 3 4 5 Years 55 33 25 17 15 12 190 125 94 83 63 47 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 At risk 3 cycles 2 cycles 0 1 2 3 4 5 Years 55 42 32 19 16 12 190 143 108 95 70 54 PFS Survival HR = 1.44 (0.99-2.0) HR = 1.40 (0.96-2.0) p = 0.05 p = 0.07 Bourhis et al Lancet Oncol 2012

Gortec 99-02 trial, 2 versus 3 cycles (patients who received at least 68 Gy) 1.00 1.00 0.90 2 chemo cycles 0.90 0.80 2 chemo cycles 3 chemo cycles 0.80 3 chemo cycles 0.70 0.70 0.60 0.60 0.50 0.40 2 cycles 0.50 0.40 0.30 2 cycles 0.30 0.20 0.10 3 cycles 0.20 0.10 0.00 3 cycles 0.00 0 1 2 3 4 5 0 1 2 3 4 5 At risk Years At risk Years 55 38 28 18 15 12 55 36 27 18 16 12 190 134 104 89 69 51 190 129 95 86 64 49 Locoregional failures HR = 1.52 (0.92-2.5) p = 0.09 Distant metastases HR = 1.82 (0.99-3.3) p = 0.05 Bourhis et al Lancet Oncol 2012

Which type of concomitant CT-RT? (I) Which drugs? Increasing the dose intensity of RT?

CT-RT +..? Adaptive RT RT-CT Altered fractionation Induction CT Cetuximab + RT + 13% + 10%?

CT-RT : No gain by increasing the dose intensity of RT Probability of loco-regional progression Patients at risk 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 Very accelerated RT alone Accelerated RT + 2 cycles CT Conventional RT + 3 cycles CT 0 1 2 3 4 5 6 Years 278 174 127 103 81 52 17 279 161 118 93 75 48 17 280 140 100 91 70 55 17 Bourhis J, et al. Lancet Oncol 2012.

Which type of concomitant CT-RT? (I) Which drugs? Decreasing the dose of RT?

Small variations in dose major impact 70 Gy + Cisplatin, N= 840 patients randomized 100 Estimated percentage locoregional failure-free (Peters JCO 2010) 80 60 40 20 0 2P < 0.0001 compliant plan by TMC no adv impact adv impact 0 1 2 3 4 Years following end of radiotherapy < 10% PTV Less than 66.5 Gy > 10% of PTV Less than 66.5 Gy

No compromize with the dose of RT +++ but can we decrease safely the volume of RT? to decrease side effects?

Evolution of SCCHN radiotherapy 2-D 3-D IMRT / 4D 1960 1990 2010 < 1950

GTV 70 Gy = 44 cc

High risk 70 Gy (+ 5 mm) = 93 cc

Elective 50 Gy = 879 cc Tomotherapy)

50Gy 3D conformal RT = 1489 cc

Gain with IMRT Nutting et al, Lancet Oncol 2011 The PARSPORT trial

Advances in radiotherapy for HNC 1) Lessons from randomized trials 2) IMRT : beyond parotid sparing? 3) New approaches?

Beyond Parotid sparing : parotid stem cells sparing? Region of major salivary ducts most radiosensitive part stem cells located along salivary ducts (mouse, rat, humans) C-kit positive cells Van Luijk, et al. ESTRO 2012

Stem-cell sparing IMRT Planning comparison study Based on planning comparison: expected reduction severe xerostomia (<25% salivary at baseline): 50% <20% Van Luijk, et al. ESTRO 2012

Ongoing randomized trial (Groningen, Netherland) N = 102 HNC patients randomized Stem-cell sparing IMRT Standard whole parotid sparing IMRT

Prevention of Dysphagia RT Dose to the pharyngeal constrictor muscles (PCM) = variable for tube feeding dependence DOSE VOLUME PARAMETERS OTHER FACTORS Sex Age Tumour-stage Nodal-stage RT technique Chemotherapy Fractionation Site Baseline dysphagia Weight loss Christianen, et al. Radiother Oncol 2012

Swallowing sparing IMRT Translation from DOSE reduction to RISK reduction NTCP (%) 70% 60% 50% 40% 30% Dmean supraglottic = 10 Gy Dmean supraglottic = 20 Gy Dmean supraglottic = 30 Gy Dmean supraglottic = 40 Gy Dmean supraglottic = 50 Gy Dmean supraglottic = 60 Gy Dmean supraglottic = 70 Gy St-IMRT SW-IMRT 20% 10% 0% 0 10 20 30 40 50 60 70 Mean dose PCM superius Van der Laan, et al. Radiother Oncol 2011

Carotid sparing IMRT : example in early glottic cancer Bilateral carotid dose V35 (ml) Mean, SD Range Median V50 (ml) Mean, SD V63 (ml) Mean, SD 0.45, 0.37 0.0-0.98 0.16 0.0, 0.0 0.0, 0.0 N = 23 patients treated at CHUV Median Follow-up = 4 years, Local control = 100%

Uni or bilateral radiotherapy? - Well (very) lateralized tumors - Minimal nodal involvement - Other than base of tongue & soft palate tumors

The future : Adaptive RT with molecular imaging 2-D 3-D IMRT / 4D Dose Painting Molecular imaging 2010 > 2015 1960 1990 < 1950

Advances in radiotherapy for HNC 1) Lessons from randomized trials 2) IMRT : beyond parotid sparing? 3) New approaches?

De-escalation for HPV? Molecular targeted agents What else Can be Optimized? Induction CT? Immunotherapy

De-escalation for HPV? Molecular targeted agents What else Can we Optimize? Induction CT? Immunotherapy

ECOG 1308 : HPV+ specific randomized trial

RTOG 1016 - Cetuximab-RT vs. CT-RT if HPV(+) Eligibility OPC P16 (+) Stage III / IV R A N D O M IZ E RT 70 Gy/35f/6 wks + cisplatin x 2 RT 70 Gy/35f/6 wks + cetuximab for 8 wks

De-escalation for HPV? Molecular targeted agents What else Can be Optimized? Induction CT? Immunotherapy

New insights for induction? Phase III randomized study TPF* cetuximab + RT vs carboplatin + 5-FU + RT Progression-free survival (%) 100 80 60 40 20 PFS (primary endpoint) TPF * cet + RT CRT T2 4, N2b c N3 LA SCCHN At risk: 0 0 1 2 3 4 5 6 Time since random assignment (years) 89 87 59 57 32 33 16 16 6 2 179 181 CRT TPF cet + RT 1. www.clinicaltrials.gov/ct2/show/nct 01233843; 2. Geoffrois L, et al. ASCO 2016 (Abstract No. 6000)

TPF related mortility in randomized trials TPF related Mortality (%) 8 7 6 7% 5 4 3 2 1 0 0%

TPF related mortility in randomized trials TPF related Mortality (%) 8 7 6 5 4 3 2 1 0 Larynx preservation Nasopharynx Larynx preservation Locally advanced Locally advanced N2-N3

TPF related mortility in randomized trials TPF related Mortality (%) 8 7 6 5 4 Larynx preservation Locally advanced Locally advanced N2-N3 3 2 1 0 Larynx preservation Nasopharynx Co-morbidies

De-escalation for HPV? Molecular targeted agents What else Can we Optimize? Induction CT? Immunotherapy

Clinical trials of molecular targeted therapies in HNSCC EGFr targeting Vandetanib Zalutumumab Erolitinib Afatinib Lapatanib Gefitinib AMPK activator PDK inhibitor Nilotinib (c kit) MEK inhibitor Trametinib Panitumumab Nimotuzumab Approved Cetuximab Nimorazole Celecoxib COX2 inhib Phase I-II Phase III Tirapazamine MET/VEGFR inhibitor Foretinib MET, VEGFR-2 E7050/Golvatinib MET inhibitor LY2801653 ONYX-015 p53 Advexin p53 Pazopanib PI3K inhibitor PX866, BKM120, BYL719, Rigosertib Sunitinib Bevacizumab Sorafenib Axitinib AKT inhibitor MK2206 mtor inhibitor Rapamycin Everolimus Temsirolimus V-EGF inhibitors Others

Clinical trials of molecular targeted therapies in HNSCC Phase I-II EGFr targeting AMPK activator PDK inhibitor Nilotinib (c kit) Vandetanib Zalutumumab Erolitinib Afatinib Lapatanib Gefitinib Nimotuzumab MEK inhibitor Panitumumab Phase III Approved Cetuximab Pazopanib Sunitinib Bevacizumab Sorafenib Axitinib AKT inhibitor mtor inhibitor V-EGF inhibitors MET inhibitor PI3K inhibitor Others

Randomized Phase III trials testing EGFr targeting in HNSCC : cetuximab is the exception (and ---does not work with CT-RT RTOG 05-22 ) Compound Mechanism of action outcome Gefitinib EGFR TKI negative Erlotinib EGFR TKI negative Afatinib EGFR/HER2 TKI Ongoing Cetuximab EGFR Chimeric MAb positive Panitumumab EGFR Humanized MAb negative Zalutumumab EGFR MAb negative Lapatinib EGFR/HER2 TKI negative The only EGFr targeting agent working (ADCC?)

CT-RT +..? Adaptive RT RT-CT Altered fractionation Induction CT Cetuximab + RT + 13% + 10%?

Adding cetuximab to CT-RT? RTOG H05-22 : Phase III (940 pts) R Stage III-IV A N D O M I Z RT + CDDP RT + CDDP + cetuximab The addition of cetuximab to RTcisplatin : - No benefit in PFS / OS. - More mucositis and skin reactions E

Adding chemotherapy to cetuximab-rt? GORTEC 2007-01 = Treatment intensification with a cetuximab backbone. 54 1. www.clinicaltrials.gov/ct2/show/nct00609284; 2. Bourhis J, et al. ASCO 2016 (Abstract No. 6003) * Off-label regimen for Erbitux

GORTEC 2007-01 Progression-free-survival 1.00 0.80 0.60 0.40 0.20 0.00 No. at risk: CT-cetux-RT** 20 Cetux-RT 4 20 1 Progression-free survival 0 1 2 3 4 5 Years since randomization 14 4 12 1 11 5 97 Median follow-up of 4.4 years (CT-cetux-RT), 4.6 years (cetux-rt) *HR adjusted for N (0 vs 1 2), T (0 2 vs 3 4) and center in Cox model 3 0 6 8 5 3 4 4 HR* 0.73 (0.57 0.94) 2-sided log-rank p=0.015 2 9 1 7 CT-Erbitux-RT** Erbitux-RT Primary endpoint met (PFS) PFS at 3 years (95% CI): CT-Erbitux-RT** 52.3% (45 59) Erbitux-RT 40.5% (34 48) 55 ** Off-label regimen for Erbitux Bourhis J, et al. ASCO 2016 (Abstract No. 6003)

Optimisation of RT-CT Locally Advanced HNSCC New molecular targeted agents New induction CT Combination with Immunotherapy

PD-1 inhibitors = the highest response rate of any single-agent immunotherapy, Activated T cell Inhibitors of PD-1 and PD-L1 prevent the tumour cell from binding to PD-1, enabling the T cell to remain active.

State of the art for radiotherapy of SCCHN - RT-CT : - RT-CT = a Standard of care - Importance of RT / CT dose and of RT-QA & IMRT - No need to increase the dose-intensity of RT - Beyond parotid sparing? - New approaches - Induction CT? - HPV / de-escalation? - New combinatory approaches with immunotherapy